Loss of RPA1 impairs peripheral T cell homeostasis and exacerbates inflammatory damage through triggering T cell necroptosis

The peripheral T cell pool is maintained at dynamic homeostasis throughout life. This is achieved through fine-tuning of thymic output and self-renewal of naïve T cells. Dysregulation of T cell homeostasis has been implicated in autoimmune diseases, yet little is known about the homeostatic mechanisms. Here, we report that the replication protein A1 (RPA1) is upregulated during T cell activation. Utilizing T cell-specific Rpa1-deficient (Rpa1fl/fl Cd4-cre) mice, we find that loss of Rpa1 restrains peripheral CD8+ T cell population and limits TCR repertoire diversity. Clinical analysis reveals that the mRNA level of RPA1 is reduced in patients with ulcerative colitis. Accordingly, Rpa1fl/fl Cd4-cre mice exhibit increased susceptibility to inflammatory diseases, including colitis and hepatitis. Mechanistically, RPA1 deficiency triggers necroptotic T cell death following TCR engagement, which in turn results in damage-associated molecular patterns (DAMPs) leakage and leukocyte recruitment, consequently exacerbating inflammatory damage. These studies thus uncover that RPA1 acts as a guardian of T cell clonal expansion that is essential for T cell homeostasis. Overall design: Study of colon infiltration immune cells from WT or CKO mice in the context of experimental colitis using 10x scRNA-seq technologies.